Severe Sepsis During Treatment for Childhood Leukemia and Sequelae Among Adult Survivors

Key Points Question Is severe sepsis during treatment for childhood leukemia associated with subsequent development of chronic health problems in adult survivors? Findings In 644 adult survivors of childhood leukemia, severe sepsis during treatment was associated with significantly higher rates of moderate to severe neurocognitive dysfunction. Sepsis was not associated with other identified chronic health conditions. Meaning Severe sepsis during childhood cancer treatment might increase the risk of clinically meaningful long-term neurocognitive problems, but more research is needed to validate these findings, identify potential mechanisms, and develop ameliorative interventions.


eMethods. Data Collection
[3][4] Neurocognitive dysfunction was also graded according to the modified CTCAE, with Z-scores based on population normative data, so that a Z-score of ≤-3 (Grade 3) represents the lowest 0.13% of the population; a Z-score ≤ -2 and > -3 (Grade 2) the next highest 2.15%; and a Z-score of ≤ -1 and > -2 (Grade 1) the next highest 13.59%, as previously described. 3rvivors who had completed a SJLIFE campus visit but subsequently died were eligible, but those who died prior to inception of SJLIFE or living patients not enrolled in SJLIFE were ineligible.
Sepsis episodes occurring during therapy for leukemia were classified using modified consensus criteria as shown in eTables 1 and 2. 5 Because blood gas measurements were not routinely available, and availability bias might affect the classification of sepsis, either PaO2 or SaO2 were used for evaluation. 6Chart reviewers were not aware of longterm chronic conditions or of neurocognitive outcomes at the time of data collection or sepsis classification.eTable 1. Definition of Severe Sepsis (Includes Septic Shock) 5

Severe sepsis:
Sepsis (systemic inflammatory response syndrome plus suspected or proven infection) plus one of the following: cardiovascular organ dysfunction OR acute respiratory distress syndrome OR 2 or more other organ dysfunctions Septic shock:

Sepsis plus cardiovascular organ dysfunction
Adapted from Goldstein B, Giroir B, Randolph A, et.al, "International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics" eTable 2. Organ Dysfunction Criteria for Classification of Severe Sepsis 5,6 Cardiovascular dysfunction: Despite administration of isotonic intravenous fluid bolus ≥40 mL/kg in 1 hour:

Domain Grading Source Grading Rubric Attention deficit
Performance on neuropsychological testing of attention, including sustained attention and focused attention.Impairment not explained by slow processing speed.
1: Performance on a task is > 1 but < 2 SD below the mean AND no functional impairment 2: Participant is prescribed medication to address attention impairment (i.e.stimulant); performance on a task is > 2 but < 3 SD below the mean OR performance on a task is > 1 but < 2 SD below the mean AND functional impact on instrumental activities.
Examples include, but are not limited to: special education services at school (IEP, 504 plan, NOT Self-contained), unable to adequately complete testing due to attention impairments, difficulty in educational/occupational settings due to attention 3: Performance on a task is > 3 SD below the mean OR performance on a task is > 1 but < 3 SD below the mean AND functional impact on self-care activities.Examples include, but are not limited to: unable to live independently due to inattention, unable to work due to inattention, self-contained classroom 4: Not applicable 5: Not applicable *Note: we do not code current medication for attention, but do indicate next to the assigned grade.

Processing speed deficit
Performance on neuropsychological testing of information processing speed and fluency.Fluency problems must not be accompanied by impairment on other measures of executive function.
1: Performance on a task is > 1 but < 2 SD below the mean AND no functional impairment 2: Performance on a task is > 2 but < 3 SD below the mean OR performance on a task is > 1 but < 2 SD below the mean AND functional impact on instrumental activities.
Examples include, but are not limited to: special education services at school (IEP, 504 plan, NOT Self-contained), unable to reach educational/occupational goals secondary to cognitive impairment, Assistance needed completing tasks at home, scheduling/ attending appointments 3: Performance on a task is > 3 SD below the mean OR performance on a task is > 1 but < 3 SD below the mean AND functional impact in self-care activities.Examples include, but are not limited to: unable to live independently, unable to work, selfcontained classroom 4: Not applicable 5: Not applicable Memory deficit Performance on neuropsychological testing of memory, including short-term verbal memory, new verbal learning, delayed verbal memory, and visual memory.Impairment not explained by attention deficits.
1: Performance on a task is > 1 but < 2 SD below the mean AND no functional impairment 2: Performance on a task is > 2 but < 3 SD below the mean OR performance on a task is > 1 but < 2 SD below the mean AND functional impact on instrumental activities.
Examples include, but are not limited to: special education services at school (IEP, 504 plan, NOT Self-contained), unable to reach educational/occupational goals secondary to memory impairment, assistance needed completing tasks at home, scheduling/ attending appointments, secondary to memory impairment © 2024 Goggin KP et al.JAMA Network Open.

Domain Grading Source
Grading Rubric 3: Performance on a task is > 3 SD below the mean OR performance on a task is > 1 but < 3 SD below the mean AND functional impact on self-care activities.Examples include, but are not limited to: unable to live independently due to memory impairment, unable to work due to memory impairment, self-contained classroom 4: Not applicable 5: Not applicable Executive function deficit Performance on neuropsychological testing of executive functions, including measures of cognitive flexibility/shifting, verbal fluency/initiation, working memory, and self-monitoring.
1: Performance on a task is > 1 but < 2 SD below the mean AND no functional impairment 2: Performance on a task is > 2 but < 3 SD below the mean OR performance on a task is > 1 but < 2 SD below the mean AND functional impact on instrumental activities.
Examples include, but are not limited to: special education services at school (IEP, 504 plan, NOT Self-contained), unable to reach educational/occupational goals secondary to cognitive impairment, assistance needed completing tasks at home, scheduling/ attending appointments 3: Performance on a task is > 3 SD below the mean OR performance on a task is > 1 but < 3 SD below the mean AND functional impact in self-care activities.Examples include, but are not limited to: unable to live independently, unable to work, selfcontained classroom 4: Not applicable 5: Not applicable Visuospatial deficit Performance on neuropsychological testing of finemotor dexterity and visual-motor integration.Impairment not explained by visual deficits or slow processing speed.
1: Performance on a motor skills task is > 1 but < 2 SD below the mean AND no functional impairment 2: Performance on a motor skills task is > 2 but < 3 SD below the mean OR performance on a motor skills task is > 1 but < 2 SD below the mean AND functional impact in instrumental activities.Examples include, but are not limited to: motor weaknesses impact performance across other cognitive domains, unable to keep up with handwriting demands, unable to prepare meals secondary to motor impairment 3: Performance on a motor skills task is > 3 SD below the mean OR performance on a motor skills task is > 1 but <

eTable 4 . 5 . 6 .
Neuropsychological Health Event Grading in the St Jude Lifetime Cohort Study eTable Incidence of Chronic Health Conditions by History of Severe Sepsis During Therapy for Leukemia: Alternative Analysis Approach eTable Neurocognitive Impairment by History of Severe Sepsis During Therapy for Leukemia: Alternative Analysis Approach eReferences This supplementary material has been provided by the authors to give readers additional information about their work.
3 Decrease in blood pressure (BP) <5 th percentile for age or systolic BP <2 SD below normal for Need for nonelective invasive or noninvasive mechanical ventilation ARDS: must include PaO2/FiO2 ratio ≤ 200 mm Hg, bilateral infiltrates, acute onset, and no evidence of left heart failure.If arterial blood gas was not obtained, SpO2/FiO2 ≤213 (if SpO2 <97%) could be substituted.6NeuropsychologicalHealthEvent Grading in the St Jude Lifetime Cohort Study3 3: Severe symptoms, associated with hypoxia, right heart failure; oxygen indicated 4: Life-threatening consequences; urgent intervention indicated (e.g., ventricular assist device); heart transplant indicated 5: Death Right heart failure Definition (event): cor pulmonale (right heart failure) Grades (2-5 same as RV systolic dysfunction): 1: Asymptomatic with laboratory(e.g., BNP) or cardiac imaging abnormalities 2: Symptoms with mild to moderate activity or exertion 3: Severe symptoms, associated with hypoxia, right heart failure; oxygen indicated 4: Life-threatening consequences; urgent intervention indicated (e.g., ventricular assist device); heart transplant indicated 5: Death Pulmonary hypertension Definition (event): Pulmonary hypertension (confirmed by cardiac catheterization) Grades: 1: Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental ADL 3: Severe or medically significant but not immediately life threatening; hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-care ADL 4: Life-threatening consequences; urgent intervention indicated 5: Death Myocardial infarction Definition (2 events for same grading rubric): Acute myocardial infarction, Coronary artery disease Grades: 1: Not applicable 2: Asymptomatic and cardiac enzymes minimally abnormal and no evidence of ischemic ECG changes 3: Severe symptoms; cardiac enzymes abnormal; hemodynamically stable; ECG changes consistent with infarction (Q waves) 4: Life-threatening consequences; hemodynamically unstable (CABG or angioplasty) 5: Death Obstructive pulmonary deficit Definition (event): Chronic obstructive pulmonary disease Includes: emphysema, chronic bronchitis, and chronic obstructive asthma Grades: 1: Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated 2: Moderate; minimal, local or noninvasive intervention indicated or initiated (inhaled medications); limiting age-appropriate instrumental ADL 3: Severe or medically significant but not immediately life-threatening (e.g., requiring supplementation of oxygen, systemic corticosteroids, BIPAP, or CPAP); hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-care ADL 4: Life-threatening consequences; urgent intervention indicated 5: Death Restrictive pulmonary deficits Definition (event): Total lung capacity (TLC) decreased.Defined by TLC < 75%.eTable 4.
3 SD below the mean AND functional impact in selfcare activities.Examples include, but are not limited to: unable to dress self, unable to feed self, unable to bathe self 4: Not applicable 5: Not applicable Neurocognitive assessments used in participants: Ataxia/fine motor dexterity (Digit-Symbol Coding, Grooved Pegboard, Trail Making Test Parts A and B, Symbol Search, Visual Memory); Cognitive disturbanceexecutive dysfunction (Trail Making Test Part B, Controlled Oral Word Association Test, Digit Span Backwards, Continuous Performance Test-II perseverations or commissions); Cognitive disturbanceprocessing speed (Symbol Search, Controlled Oral Word Association Test); Concentration impairment (Continuous Performance Test-II omissions or variability, Trail Making Test Part A, Symbol Search, Digit Span Forward); Memory impairment (Digit Span Forward, California Verbal Learning Test-II learning slope or long-delay free recall, Visual Selective Reminding) eTable 5. Incidence of Chronic Health Conditions by History of Severe Sepsis During Therapy for Leukemia: Alternative Analysis Approach Neurocognitive Impairment by History of Severe Sepsis During Therapy for Leukemia: Alternative Analysis Approach , Unadjusted Hazard Ratio; aHR, adjusted hazard ratio; 95% CI, 95% confidence interval.Models are adjusted for propensity score weights, including radiation exposure, cumulative doses of vincristine, intrathecal methotrexate, intravenous/oral methotrexate, high-dose methotrexate, alkylating agents, anthracyclines, asparaginase, corticosteroids and epipodophyllotoxins, age at diagnosis, and year of diagnosis.*P values adjusted for false discovery rate based on 21 comparisons Models adjusted for propensity score weights including radiation exposure, cumulative doses of vincristine, intrathecal methotrexate, intravenous/oral methotrexate, high dose methotrexate, alkylating agents, anthracyclines, asparaginase, corticosteroids and epipodophyllotoxins, age at diagnosis, and year of diagnosis.*p-values adjusted for false discovery rate based on 21 comparisons eTable 6. uHR